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Chronic blood transfusion is increasingly indicated in patients with sickle cell disease. Measuring resulting iron overload remains a challenge. Children without viral hepatitis enrolled in 2 trials for stroke prevention were examined for iron overload (STOP and STOP2; n = 271). Most received desferrioxamine chelation. Serum ferritin (SF) changes appeared nonlinear compared with prechelation estimated transfusion iron load (TIL) or with liver iron concentrations (LICs). Averaged correlation coefficient between SF and TIL (patients/observations, 26 of 164) was r = 0.70; between SF and LIC (patients/observations, 33 of 47) was r = 0.55. In mixed models, SF was associated with LIC (P = .006), alanine transaminase (P = .025), and weight (P = .026). Most patients with SF between 750 and 1500 ng/mL had a TIL between 25 and 100 mg/kg (72.8% +/- 5.9%; patients/observations, 24 of 50) or an LIC between 2.5 and 10 mg/g dry liver weight (75% +/- 0%; patients/observations, 8 of 9). Most patients with SF of 3000 ng/mL or greater had a TIL of 100 mg/kg or greater (95.3% +/- 6.7%; patients/observations, 7 of 16) or an LIC of 10 mg/g dry liver weight or greater (87.7% +/- 4.3%; patients/observations, 11 of 18). Although SF changes are nonlinear, levels less than 1500 ng/mL indicated mostly acceptable iron overload; levels of 3000 ng/mL or greater were specific for significant iron overload and were associated with liver injury. However, to determine accurately iron overload in patients with intermediately elevated SF levels, other methods are required. These trials are registered at www.clinicaltrials.gov as #NCT00000592 and #NCT00006182.

Microalbuminuria (MA) and proteinuria (P) are believed to be precursors of sickle cell nephropathy. We analyzed our longitudinal data on MA/P in children with sickle cell disease (SS) to define the age of onset, association with age, sex, and hemoglobin, and to explore the safety and efficacy of hydroxyurea and angiotensin converting enzyme inhibitor (ACEI) therapy. Data on 191 patients with SS (ages 3 to 20 y) with a mean follow up of 2.19 years+/-2.05 were available. Urine MA was measured yearly with follow-up testing if abnormal. Prevalence of MA/P was 19.4%. Increasing age and lower hemoglobin levels were related to MA/P but sex was not. Microalbumin excretion normalized in 44% of patients treated with hydroxyurea and 56% of patients treated with ACEI. Hyperkalemia developed in 4 ACEI patients resulting in discontinuation of treatment in 3 children. In summary, MA/P often develops in childhood and preventive and treatment strategies for sickle cell nephropathy should be a focus of pediatric programs. Our preliminary data suggest that although both hydroxyurea and ACEI therapy may be beneficial for MA/P, hyperkalemia may limit the utility of ACEI.

Purpose: To determine the prevalence of microalbuminuria and to establish clinical characteristics associated with microalbuminuria in children with sickle cell anemia., Patients and Methods: Urine samples of all children (homozygous SS) followed in the Medical College of Georgia's Children's Medical Center Sickle Cell Clinic were screened for microalbuminuria. Random samples were obtained from continent patients at routine office visits between September 1996 and November 1999. A retrospective chart survey was performed to determine clinical correlates for microalbuminuria. Medical records were reviewed for age, sex, hemoglobin, and episodes of pneumonia, pain, aplasia, acute chest syndrome, priapism, and avascular necrosis. Demographic and clinical variables were compared with microalbuminuria by univariate and multivariate logistic regression., Results: One hundred forty-two patients ages 21 months to 20 years made up the study group. The prevalence of microalbuminuria was 19%. Both increasing age and a lower hemoglobin level were found to correlate with microalbuminuria. By multivariate analysis, boys with microalbuminuria were likely to have a lower hemoglobin level and girls with microalbuminuria were likely to be older. None of the following factors were significantly related to microalbuminuria: pain, pneumonia, acute chest syndrome, priapism, avascular necrosis, or aplastic episodes., Conclusions: Microalbuminuria is strongly and directly related to age and strongly and inversely related to hemoglobin levels. Identification of risk factors for microalbuminuria may allow earlier intervention to prevent renal complications in patients with sickle cell disease.

We have studied three sickle cell anemia patients who also carried a heterozygosity for one of the following alpha chain abnormalities: Hb G-Philadelphia [alpha 68(E17)Asn-->Lys], Hb Montgomery [alpha 48 (CE6)Leu-->Arg], and Hb Chicago [alpha 136(H19)Leu-->Met]. Electrophoretic analyses alone may result in incomplete and incorrect information. Confirmation of the diagnosis of Hb SS or Hb SC disease by one of the fast high performance liquid chromatographic procedures is recommended.

Anecdotal reports have attributed persistent splenomegaly in African sickle cell anemia (SS) patients to the effects of malaria. However, no comparative studies of patients in malarial and nonmalarial regions have been conducted, and few studies of malaria antibody titers have been reported. In the present study, age- and sex-matched Nigerian patients (n = 310), while it was found only in 8% of U.S. patients (n = 100) from Georgia. There was significant linear correlation between spleen size and Hb levels and with serum immunoglobulins in the Nigerian group. However, serum complement levels (C3 and C4) were not affected by spleen size. In both groups, patients with splenomegaly had fewer circulating pitted red cells than their counterparts without splenomegaly. The mean +/- SE of IgG-specific malaria antibody titer among the Nigerian patients without palpable spleens was 9,386 +/- 2,036; 9,334 +/- 2,980 in those with spleens between 1 and 5 cm, 16,201 +/- 4,502 in those with spleens between 6 and 10 cm, and 22,445 +/- 8,456 in those with spleens above 10 cm. Coexistent alpha-thalassemia did not influence the prevalence of splenomegaly among the Nigerian SS patients. This study provides additional evidence that malaria plays a significant role in the persistence of splenomegaly in African patients.

We have studied two babies with Hb H disease from birth to about six months of age and analyzed the changes in the relative quantities of the five globin chains (zeta, alpha, beta, G gamma, A gamma) and the four hemoglobins (Hb F, Hb A, Hb Bart's, Hb H) using different high performance liquid chromatography procedures. The types of Hb H disease were -(SEA)/-alpha(3.7 kb) and -(Fil)/-alpha(3.7 kb); the larger -(Fil) deletion includes the functional zeta 2-globin gene, explaining the higher zeta chain level in the baby with the -(SEA)/-alpha(3.7 kb) type. The functional hemoglobin level at birth (Hb A+Hb F) was 11 to 12 g/dl with 3 to 4 g/dl Hb Bart's (gamma 4). Only 5% of the "fast-moving" hemoglobin was Hb H (beta 4). The level of Hb F at birth was low (less than 50% of the total Hb A+Hb F). After birth, the alpha and gamma chain production decreases rapidly resulting in a severe anemia (total functional hemoglobin approximately 7 g/dl) at 30 to 60 days postnatally, improving gradually to 8.5-9.5 g/dl at age of three months. The preferential formation of Hb A over Hb F at birth, and presumably prenatally, has the advantage that the level of the highly unstable Hb H is kept low; it also results in low levels of Hb F impairing the oxygen transfer capability of the fetal blood.

The silent Hb Muscat with a Leu----Val replacement at position beta 32 was discovered by reversed phase high performance liquid chromatography in two members of an Arabian family from Oman; in one person Hb Muscat occurred with Hb S and in the other with Hb A. Hb Muscat is slightly unstable but its presence has no apparent adverse effect on the health of its carriers. Additional hemoglobin abnormalities observed in this family were a common alpha-thalassemia-2 (-3.7 kb) and Hb S. The beta S haplotypes in the heterozygous carriers and the two sickle cell anemia patients were #19 (Benin) and #20 (Bantu); the latter likely originated from an East African population.

An extension of previous reports describing the molecular defects and hematological abnormalities in black patients with Hb S(C) beta-thalassemia living in the Southeastern United States is presented. As many as 58 patients with Hb S-beta(+)-thalassemia, 16 with Hb C-beta(+)-thalassemia and 12 with Hb S-beta(0) -thalassemia have been studied. Patients with Hb S(C) beta(+)-thalassemia type 2 (high Hb A values) were most common; the thalassemia was due to mutations in the promoter of the beta-globin gene [-88 (C----T) and -29 (A----G)] or at the polyadenylation signal (T----C). Two patients with lower Hb A values (type 1) carried a mutation in the first intron of the beta-globin gene (IVS-1-5: G----T). The simultaneous presence of an alpha-thalassemia -2(-alpha/) resulted in some modifications of the hematological parameters, but had a minimal effect on the clinical condition. Patients with Hb S-beta (0) thalassemia had lower hemoglobin values, lower number of red blood cells, and lower MCHC values and suffered more frequently from complications than the patients with Hb S-beta(+)-thalassemia. A total of 17 different beta-thalassemia mutations were observed in 128 chromosomes; two mild beta(+)-thalassemia mutations [-88(C----T) and -29(A----G)] account for more than 80% of the thalassemic chromosomes.

In this study, the neuropsychologic functioning of 21 children with sickle cell anemia and 21 sibling controls, age range 7 through 16 years, with no history of neurologic disease, was examined. Outcome measures included tests of intelligence, constructional praxis, memory, and academic learning. On the Wechsler Intelligence Scale for Children--Revised, the sickle cell group had a mean Full Scale IQ of 77.7 (SD 12.4) compared with 94.3 (SD 11.0) for the control group. The profile of test scores was similar for the two groups, with the sickle cell group scoring significantly lower than the control group on almost all cognitive measures. Both groups showed academic achievement to be commensurate with their measured intellectual ability. These results suggest that subtle but significant and widespread neuropsychologic deficits are associated with sickle cell anemia even in the absence of neurologic complications. When and by what process this neuropsychologic impairment is caused needs to be determined.

Through direct sequencing and dot-blot analyses with synthetic oligonucleotide probes of amplified DNA, a new nucleotide substitution was discovered in a Black teenager with severe Hb S-beta zero-thalassaemia. The substitution involved a T----C replacement at the second position of the donor splice site of the first intervening sequence of the beta-globin gene. The clinical and haematological observations made in Black subjects with Hb S-beta zero-thalassaemia, with different types of thalassaemia, suggest severe disease resembling sickle cell anaemia. Only an occasional patient had a milder clinical course, perhaps because of a greatly increased production of fetal haemoglobin.

Four types of chromosomes with a deletion between the human embryonic zeta and psi zeta globin genes were identified among 2.8% of 321 Black Americans from Georgia. Two deletions of approximately 11 kb which differed by about 300 bp occurred on chromosomes with or without a polymorphic Xba I site 5' to the zeta globin gene [(X+) or (X-)]. The deletions are identifiable in Xba I digests of genomic DNA using an alpha or a zeta globin gene probe which yield fragments of 23 kb from (X+)-zeta alpha alpha chromosomes or 27 kb from (X-)-zeta alpha alpha chromosomes. Digestion with other enzymes and probing with both alpha and zeta probes gave fragments typical of the two zeta globin gene deletions previously identified in Polynesians. Among Black Americans, these zeta globin gene deletions have been found in combination with alpha globin gene deletions in trans but not in cis. Homozygotes have not been found. Hematologic data on carriers of the zeta globin gene deletions in association with Hb AS, SS, and SC suggest that these deletions have no effect on the function of the adult alpha globin genes.

The hematology and pathophysiology of sickle cell disease during the postnatal development of younger hemoglobin (Hb) S homozygotes (SS) could be considerably affected by a variability of alpha globin gene numbers. We have documented longitudinal developmental changes of hematological values and hemoglobin composition on 147 patients with SS (alpha alpha/alpha alpha), 64 with SS (-alpha/alpha alpha), and 9 with SS (-alpha/-alpha) between the ages of 1 and 15 years. Non-steady-state data were excluded from these analyses. The number and organization of alpha globin genes was established by gene mapping. As anticipated, mean corpuscular volume and erythrocyte counts correlated with alpha globin gene numbers throughout the 15-year age interval. On the other hand, SS children with alpha alpha/alpha alpha, -alpha/alpha alpha, -alpha/-alpha had similar hemoglobin concentrations up to the ages of 5-10 years. Around the age of 7, the SS patients with -alpha/-alpha developed a higher Hb concentration than that of the SS (-alpha/alpha alpha), which in turn was higher than that of the SS (alpha alpha/alpha alpha). The emergence of this difference coincided with a developmental increase of the mean corpuscular hemoglobin concentration (MCHC) in patients with SS (alpha alpha/alpha alpha) and the decline of Hb F % under 15%. This newly observed developmental change of the MCHC could lead to increased hemolysis and anemia after the age of 5-10 years. It occurs to a smaller extent among SS (-alpha/alpha alpha) or not at all among SS (-alpha/-alpha) such that these two categories of patients have less severe hemolysis and higher hemoglobin levels at older ages. Although the proportion of Hb F was independent of alpha globin gene numbers, the absence of Hb Bart's suggested that alpha-thalassemia promotes the intracellular assembly of Hb F over Hb S tetramers. Thus, the interaction of alpha-thalassemia and Hb F in young SS patients may be more complex than revealed by Hb F levels in cell lysates. Among older SS children (greater than 7 years) alpha-thalassemia and Hb F levels exceeding 15% appear to have additive effects in diminishing the rate of hemolysis.